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Safety and Bioactivity of Ipilimumab and Nivolumab Combination Prior to Liver Resection in Hepatocellular Carcinoma (PRIME-HCC)

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ClinicalTrials.gov Identifier: NCT03682276
Recruitment Status : Recruiting
First Posted : September 24, 2018
Last Update Posted : February 15, 2021
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Imperial College London

Tracking Information
First Submitted Date  ICMJE September 20, 2018
First Posted Date  ICMJE September 24, 2018
Last Update Posted Date February 15, 2021
Actual Study Start Date  ICMJE March 1, 2019
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 21, 2018)
  • Delay to surgery [ Time Frame: Up to Day 89 ]
    Number of patients with an unplanned delay to surgery to Day 89 or later
  • Incidence of treatment-emergent adverse events [Safety and Tolerability] [ Time Frame: Up to Day 127 ]
    Safety and tolerability of the nivolumab and ipilimumab combination based on NCI CTCAE v5.0 criteria from the day of first nivolumab and ipilimumab administration to 126 days later
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 21, 2018)
  • Objective response rate [ Time Frame: Up to Day 43 ]
    Objective response rate on pre-resection imaging 42 days after the day of first nivolumab and ipilimumab administration using RECIST v1.1 criteria
  • Pathologic response rate [ Time Frame: Up to Day 88 or up to liver resection, whichever came first ]
    Pathologic response rate on hematoxylin and eosin evaluation of the resected specimen
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Bioactivity of Ipilimumab and Nivolumab Combination Prior to Liver Resection in Hepatocellular Carcinoma
Official Title  ICMJE PRIME-HCC: Preliminary Assessment of Safety and Bioactivity of the Ipilimumab and Nivolumab Combination Prior to Liver Resection (LR) in Hepatocellular Carcinoma (HCC)
Brief Summary The PRIME-HCC trial will assess the effects of combination treatment with nivolumab (OPDIVO) and ipilimumab (YERVOY) pre-operatively in hepatocellular carcinoma patients for whom liver resection is planned. The trial will be conducted at a small number of National Health Service hospitals in the UK. Participants will receive two doses of nivolumab and a single dose of ipilimumab in the weeks before their planned surgery.
Detailed Description

This is a single-arm, open-label study to be conducted in 32 patients at a small number of UK hospitals. The study is in 2 parts: Part 1 will confirm, in a small number of patients, that the treatment regimen is safe and doesn't result in unacceptable delay to liver resection. Part 2 will expand the number of patients studied, and provide the opportunity to assess survival over about 2 years after liver resection. The decision to proceed to Part 2 will be taken with advice from an independent, expert committee.

Patients with early-stage HCC will first undergo screening procedures during a 28-day time window between giving consent and starting drug treatment. Screening procedures will include:

  • Medical interview and physical exam
  • ECG
  • Tumour biopsy
  • Tumour imaging by MRI
  • Tumour imaging by CT
  • Blood and urine samples
  • Stool sample (optional)

Patients meeting the protocol-specified criteria will be enrolled and on Day 1 will have the following:

  • Medical interview, and physical exam (if required)
  • Blood and urine samples
  • Intravenous dose of ipilimumab ('YERVOY') 1 milligram per kilogram body weight
  • Intravenous dose of nivolumab ('OPDIVO') 3 milligrams per kilogram body weight

On Day 22 the participants will have the following:

  • Medical interview, and physical exam (if required)
  • Blood and urine samples
  • Intravenous dose of nivolumab ('OPDIVO') 3 milligrams per kilogram body weight

On Day 43 the participants will have the following:

  • Medical interview, and physical exam (if required)
  • ECG
  • Tumour imaging by MRI
  • Blood and urine samples
  • Stool sample (optional)

Patients who remain eligible for liver resection will likely undergo surgery within a few days of the Day 43 visit.

On Day 127 the participants will have the following:

  • Medical interview, and physical exam (if required)
  • Tumour imaging by MRI
  • Blood and urine samples

Every 4 months thereafter until 2 years later, or until starting another anti-cancer treatment, participants will have tumour imaging by MRI.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Hepatocellular Carcinoma
Intervention  ICMJE
  • Biological: Ipilimumab
    Ipilimumab is a monoclonal antibody given as an immunotherapy
    Other Name: YERVOY
  • Biological: Nivolumab
    Nivolumab is a monoclonal antibody given as an immunotherapy
    Other Name: OPDIVO
Study Arms  ICMJE Experimental: Treatment Group
Ipilimumab, solution for infusion, 1 milligram per kilogram body weight, once every 3 weeks, for 3 weeks; Nivolumab, solution for infusion, 3 milligrams per kilogram body weight, once every 3 weeks, for 6 weeks
Interventions:
  • Biological: Ipilimumab
  • Biological: Nivolumab
Publications * Pinato DJ, Cortellini A, Sukumaran A, Cole T, Pai M, Habib N, Spalding D, Sodergren MH, Martinez M, Dhillon T, Tait P, Thomas R, Ward C, Kocher H, Yip V, Slater S, Sharma R. PRIME-HCC: phase Ib study of neoadjuvant ipilimumab and nivolumab prior to liver resection for hepatocellular carcinoma. BMC Cancer. 2021 Mar 23;21(1):301. doi: 10.1186/s12885-021-08033-x.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 21, 2018)
32
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 1, 2022
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Written informed consent for the trial.
  2. Aged ≥18 years
  3. Confirmed diagnosis of HCC
  4. Willing to provide tissue from an excisional biopsy of a tumour lesion
  5. Have measurable disease by Computed Tomography (CT)-scan or Magnetic Resonance Imaging (MRI) defined by RECIST 1.1 criteria
  6. Ineligible for liver transplantation
  7. Medically fit to undergo surgery as determined by the treating medical and surgical oncology team
  8. ECOG performance status 0 or 1
  9. Adequate organ function
  10. Overall Child-Pugh class A
  11. Female patient of childbearing potential should have a negative serum pregnancy test within 24 h of her first dose of IMP
  12. Women of childbearing potential must be willing to use a highly effective method of contraception for the course of the study through 5 months after the last dose of Investigational Medicinal Product (IMP). Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient.
  13. Sexually active males must agree to use an adequate method of contraception starting with the first dose of IMP through 7 months after the last dose of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient.

Exclusion Criteria:

  1. Extrahepatic metastasis
  2. Prior systemic anticancer treatment for HCC, including an anti-PD-1, anti-PD-L1 or anti-CTLA-4 antibody
  3. Prior orthotopic liver transplantation
  4. Any major surgery within the 3 weeks prior to enrolment
  5. Hepatic encephalopathy
  6. Ascites that is refractory to diuretic therapy
  7. Is currently receiving anti-cancer therapy (chemotherapy, radiation therapy, immunotherapy or biologic therapy) or has participated or is participating in a study of an IMP or used an investigational device within 4 weeks of the first dose of IMP
  8. Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy
  9. Known history of active Bacillus Tuberculosis (TB)
  10. History of known hypersensitivity to any monoclonal antibody or any of their excipients
  11. Known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical cancer
  12. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
  13. Known history of, or any evidence of active, non-infectious pneumonitis
  14. Active infection requiring systemic therapy, with exceptions relating to Hepatitis B and C virus infection
  15. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating Principal Investigator (PI)
  16. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
  17. Pregnant or breastfeeding
  18. Known history of Human Immunodeficiency Virus (HIV; HIV 1/2 antibodies)
  19. Received a live vaccine within 30 days of first dose of IMP administration. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: David J Pinato 02033131151 d.pinato@imperial.ac.uk
Contact: Frances Abomeli 02033138070 f.abomeli@imperial.ac.uk
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03682276
Other Study ID Numbers  ICMJE C/36/2017
2018-000987-27 ( EudraCT Number )
CA209-9LC ( Other Identifier: Bristol-Myers Squibb )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Imperial College London
Study Sponsor  ICMJE Imperial College London
Collaborators  ICMJE Bristol-Myers Squibb
Investigators  ICMJE
Principal Investigator: David J Pinato Imperial College London
PRS Account Imperial College London
Verification Date February 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP